JP2007520522A - Combination of (a) DNA topoisomerase inhibitor and (b) IAP inhibitor - Google Patents
Combination of (a) DNA topoisomerase inhibitor and (b) IAP inhibitor Download PDFInfo
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- JP2007520522A JP2007520522A JP2006551818A JP2006551818A JP2007520522A JP 2007520522 A JP2007520522 A JP 2007520522A JP 2006551818 A JP2006551818 A JP 2006551818A JP 2006551818 A JP2006551818 A JP 2006551818A JP 2007520522 A JP2007520522 A JP 2007520522A
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- Prior art keywords
- inhibitor
- combination
- iap
- topoisomerase
- compound
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
本発明は、(ａ)ＤＮＡトポイソメラーゼ阻害剤化合物および(ｂ)アポトーシス阻害タンパク質(ＩＡＰ)のカスパーゼ−９阻害特性を阻害する化合物(ＩＡＰ阻害剤)を含む、増殖性疾患、とりわけ固形腫瘍疾患の処置用医薬組み合わせ剤；このような組み合わせ剤を含む医薬組成物；増殖性疾患処置用医薬の製造のための、このような組み合わせ剤の使用；同時、別々または連続使用のための組み合わせ製剤としてこのような組み合わせを含む商業用包装物または製品；および温血動物、とりわけヒトの処置法に関する。 The present invention relates to the treatment of proliferative diseases, particularly solid tumor diseases, comprising (a) a DNA topoisomerase inhibitor compound and (b) a compound that inhibits the caspase-9 inhibitory properties of apoptosis inhibitor protein (IAP) (IAP inhibitor). A pharmaceutical composition for such use; a pharmaceutical composition comprising such a combination; the use of such a combination for the manufacture of a medicament for the treatment of proliferative diseases; and thus as a combined preparation for simultaneous, separate or sequential use Commercial packages or products containing such combinations; and methods for treating warm-blooded animals, especially humans.
Description
本発明は、(ａ)ＤＮＡトポイソメラーゼ阻害剤化合物および(ｂ)アポトーシス阻害タンパク質(ＩＡＰ)のカスパーゼ−９阻害特性を阻害する化合物(ＩＡＰ阻害剤)、ならびに所望により少なくとも１個の薬学的に許容される担体を含む、同時、別々または連続使用のための、特に増殖性疾患、とりわけ固形腫瘍疾患の処置用医薬組み合わせ剤；このような組み合わせ剤を含む医薬組成物；増殖性疾患処置用医薬の製造のための、このような組み合わせ剤の使用；同時、別々または連続使用のための組み合わせ製剤としてこのような組み合わせを含む商業用包装物または製品；および温血動物、とりわけヒトの処置法に関する。化合物(ａ)と(ｂ)を組み合わせて使用したとき、相加効果以上のものが見られる。 The invention includes (a) a DNA topoisomerase inhibitor compound and (b) a compound that inhibits the caspase-9 inhibitory properties of an apoptosis inhibitor protein (IAP) (IAP inhibitor), and optionally at least one pharmaceutically acceptable. A pharmaceutical combination for the treatment of proliferative diseases, in particular solid tumor diseases, for simultaneous, separate or sequential use, comprising a carrier, a pharmaceutical composition comprising such a combination; manufacture of a medicament for the treatment of proliferative diseases The use of such combinations for; commercial packaging or products containing such combinations as combination formulations for simultaneous, separate or sequential use; and methods of treatment of warm-blooded animals, especially humans. When compounds (a) and (b) are used in combination, more than an additive effect is observed.
ＤＮＡトポイソメラーゼは、複製、転写、および修復を含む、多くの重要な過程中のＤＮＡの弛緩に必須の酵素である。トポイソメラーゼには２種；トポイソメラーゼＩおよびトポイソメラーゼIIがある。カンプトテシンおよび関連化合物は、トポイソメラーゼＩの最も重要な阻害剤である。 DNA topoisomerase is an essential enzyme for the relaxation of DNA during many important processes, including replication, transcription, and repair. There are two types of topoisomerase; topoisomerase I and topoisomerase II. Camptothecin and related compounds are the most important inhibitors of topoisomerase I.
カンプトテシンは下記構造の植物アルカロイドである。
最近報告されたアポトーシスを迂回するための分子機構は、ＩＡＰファミリーのメンバーの過剰発現を含む。ＩＡＰは、アポトーシスを直接カスパーゼと相互作用し、中和することにより妨害する。原型ＩＡＰであるＸＩＡＰは、ＢＩＲ１、２および３ドメインと呼ばれる３個の機能的ドメインを有する。ＢＩＲ３は、直接カスパーゼ９と相互作用し、その天然基質、プロカスパーゼ３と結合し、開裂する能力を阻害する。故に、本発明の重要な態様において、ＩＡＰ阻害剤化合物は、ＸＩＡＰのＢＩＲ３ドメインとカスパーゼ−９の相互作用を阻害する。 The recently reported molecular mechanism for bypassing apoptosis involves overexpression of members of the IAP family. IAP prevents apoptosis by directly interacting with and neutralizing caspases. XIAP, the prototype IAP, has three functional domains called BIR1, 2 and 3 domains. BIR3 directly interacts with caspase 9 and inhibits its ability to bind and cleave with its natural substrate, procaspase 3. Thus, in an important aspect of the present invention, an IAP inhibitor compound inhibits the interaction of XIAP BIR3 domain with caspase-9.
ＸＩＡＰのＢＩＲ３ドメインとカスパーゼ−９の相互作用を阻害する治療化合物は、ＳＭＡＣの摸倣体および、例えば米国特許６,３００,４９２で請求のようなアンチセンス核酸を含む。 Therapeutic compounds that inhibit the interaction of XIAP with the BIR3 domain and caspase-9 include mimics of SMAC and antisense nucleic acids as claimed, for example, in US Pat. No. 6,300,492.
ＳＭＡＣの摸倣体は、ＷＯ２００４／００５２４８に記載の化合物、特に化合物Ｃ：
本明細書で使用する用語“トポイソメラーゼII阻害剤”は、アントラサイクリン類ドキソルビシン(リポソーム製剤、例えばCAELYXＴＭ)、エピルビシン、イダルビシンおよびネモルビシン(nemorubicin)、アントラキノン類ミトキサントロンおよびロソキサントロン、ならびにポドフィロトキシン類エトポシドおよびテニポシドを含むが、これらに限定されない。 As used herein, the term “topoisomerase II inhibitor” refers to the anthracyclines doxorubicin (liposomal formulations such as CAELYX ™ ), epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and rosoxanthrone, and podophyllotoxin. The classes etoposide and teniposide include, but are not limited to:
故に、本発明はまた、(ａ)ＤＮＡトポイソメラーゼ阻害剤および(ｂ)ＩＡＰ阻害剤を含む、組み合わせ製剤または医薬組成物のような組み合わせ剤に関する。より特に、第一の態様において、本発明は(ａ)トポイソメラーゼＩ阻害剤および(ｂ)ＩＡＰ阻害剤を含む組み合わせ剤に関し、そして第二の態様において、本発明は(ａ)トポイソメラーゼII阻害剤および(ｂ)ＩＡＰ阻害剤を含む組み合わせ剤に関する。 Thus, the present invention also relates to a combination such as a combination formulation or pharmaceutical composition comprising (a) a DNA topoisomerase inhibitor and (b) an IAP inhibitor. More particularly, in a first aspect, the invention relates to a combination comprising (a) a topoisomerase I inhibitor and (b) an IAP inhibitor, and in a second aspect, the invention relates to (a) a topoisomerase II inhibitor and (b) relates to a combination comprising an IAP inhibitor.
本明細書で使用する用語“組み合わせ製剤”は、上記で定義の組み合わせパートナー(ａ)および(ｂ)を個々に独立して、または組み合わせパートナー(ａ)および(ｂ)の区別される量の異なる固定された組み合わせの使用により、すなわち同時にまたは異なる時点で投与できる点で、とりわけ“複数部分のキット”と定義する。複数部分のキットのパーツを、次いで、例えば、同時にまたは時間的にずらして、すなわち異なる時点でおよび任意の複数部分のキットに対して等しいまたは異なる時間間隔で投与できる。組み合わせパートナー(ａ)の総量の組み合わせパートナー(ｂ)に対する比率は、例えば処置すべき患者亜集団の必要性に合うように、または単独の必要性に合うように変化できる。 The term “combination formulation” as used herein refers to the combination partners (a) and (b) as defined above individually or in different amounts of the combination partners (a) and (b). In particular, it is defined as a “multipart kit” in that it can be administered by a fixed combination, ie at the same time or at different times. The parts of the multi-part kit can then be administered, for example, simultaneously or offset in time, i.e. at different times and at equal or different time intervals for any multi-part kit. The ratio of the total amount of combination partner (a) to combination partner (b) can vary, for example, to suit the needs of the patient subpopulation to be treated or to suit the needs of a single person.
本発明の一つの態様において、(ａ)トポイソメラーゼＩ阻害剤は、カンプトテシン、イリノテカンおよびトポテカンおよびある種の癌の処置に承認されている関連化合物、ＢＮＰ１３５０、ＳＮ３８、９−アミノ−カンプトテシン、ルルトテカン、ギマテカン、ジフロモテカンのような数個のホモカンプトテシン、および、２０Ｓヒドロキシまたは１０ヒドロキシを介した、例えば、例えば、カルボキシメチルデキストラン、ポリ−Ｌ−グルタミン酸、ポリエチレングリコールなどとの数個のコンジュゲート、例えばＴ−０１２８、ＤＸ−３１０、ＣＴ−２１０６およびProtecanから成る群から選択される。 In one embodiment of the invention, (a) the topoisomerase I inhibitor comprises camptothecin, irinotecan and topotecan and related compounds approved for the treatment of certain cancers, BNP1350, SN38, 9-amino-camptothecin, luruthecan, gimatecan , Several homocamptothecins such as difuromotecan and several conjugates such as carboxymethyl dextran, poly-L-glutamic acid, polyethylene glycol etc. via 20S hydroxy or 10 hydroxy, for example T- Selected from the group consisting of 0128, DX-310, CT-2106 and Protecan.
本発明の一つの態様において、(ｂ)ＩＡＰ阻害剤は、例えば米国特許６,３００,４９２で請求のようなアンチセンス核酸、ならびに例えばＷＯ２００４／００５２４８に記載のような、特に化合物Ｃおよび化合物ＤのようなＳＭＡＣの摸倣体のような、ＸＩＡＰのＢＩＲ３ドメインとカスパーゼ−９の相互作用を阻害する治療化合物から成る群から選択される。 In one embodiment of the invention, (b) an IAP inhibitor comprises an antisense nucleic acid as claimed, for example, in US Pat. No. 6,300,492, and in particular compound C and compound D, as described for example in WO 2004/005248. Selected from the group consisting of therapeutic compounds that inhibit the interaction of caspase-9 with the BIR3 domain of XIAP, such as a mimic of SMAC.
本明細書で使用する用語“処置する”または“処置”は、疾患進行遅延をもたらす処置を含む。本明細書で使用する用語“進行遅延”は、処置すべき増殖性疾患の前段階もしくは初期相にある患者への組み合わせの投与を意味し、該患者において、例えば、対応する疾患の前形態が診断されているか、例えば医学的処置または事故に起因する状態にあって対応する疾患を発症しそうな状態にある。 The term “treating” or “treatment” as used herein includes treatments that result in delayed disease progression. As used herein, the term “delayed progression” means administration of a combination to a patient in the pre-stage or early phase of a proliferative disorder to be treated, in which, for example, the corresponding pre-form of the disease is Have been diagnosed or are likely to develop a corresponding disease, for example due to medical treatment or accident.
用語“固形腫瘍”は、とりわけ乳癌、卵巣癌、結腸および一般にＧＩ(胃腸)管の癌、頸癌、肺癌、特に小細胞肺癌、および非小細胞肺癌、頭頚部癌、膀胱癌、前立腺の癌またはカポジ肉腫を意味する。本組み合わせ剤は固形腫瘍だけでなく、液性腫瘍腫瘍の増殖も阻害する。さらに腫瘍のタイプおよび使用する特定の組み合わせ剤に依存して、腫瘍容積の減少を達成できる。ここに記載の組み合わせ剤はまた、腫瘍の転移性拡散ならびに微小転移の増殖または発症の予防にも適する。ここに記載の組み合わせ剤は、特に予後不良の患者、とりわけ非小細胞肺癌を有する予後不良の患者の処置に適する。 The term “solid tumor” includes cancer of the breast, ovarian cancer, colon and generally the GI (gastrointestinal) tract, cervical cancer, lung cancer, especially small cell lung cancer, and non-small cell lung cancer, head and neck cancer, bladder cancer, prostate cancer Or Kaposi's sarcoma. The combination inhibits the growth of not only solid tumors but also humoral tumors. Furthermore, depending on the type of tumor and the particular combination used, a reduction in tumor volume can be achieved. The combinations described herein are also suitable for the prevention of metastatic spread of tumors as well as the growth or development of micrometastasis. The combinations described herein are particularly suitable for the treatment of patients with poor prognosis, especially those with poor prognosis having non-small cell lung cancer.
コード番号、一般名または商品名により同定した活性剤の構造は、標準概論“The Merck Index”の現行版またはデータベース、例えばPatents International(例えばIMS World Publications)から取り得る。それらの対応する内容は、引用により本明細書に包含させる。 The structure of the active agent identified by code number, generic name or trade name can be taken from the current edition of the standard introduction “The Merck Index” or from a database, eg Patents International (eg IMS World Publications). Their corresponding contents are hereby incorporated by reference.
組み合わせパートナー(ａ)および(ｂ)に関する言及はまた薬学的に許容される塩も含むことは理解されよう。これらの組み合わせパートナー(ａ)および(ｂ)が、例えば、少なくとも１個の塩基性中心を有するとき、それらは、酸付加塩を形成できる。対応する酸付加塩はまた、所望により、さらに塩基性中心が存在し得る。酸性基(例えばＣＯＯＨ)を有する組み合わせパートナー(ａ)および(ｂ)はまた、塩基と塩を形成できる。組み合わせパートナー(ａ)または(ｂ)もしくはそれらの薬学的に許容される塩はまた水和物の形で使用でき、または、結晶化に使用する他の溶媒を含み得る。 It will be understood that references to combination partners (a) and (b) also include pharmaceutically acceptable salts. When these combination partners (a) and (b) have, for example, at least one basic center, they can form acid addition salts. The corresponding acid addition salts can also have additional basic centers if desired. Combination partners (a) and (b) with acidic groups (eg COOH) can also form salts with bases. The combination partners (a) or (b) or their pharmaceutically acceptable salts can also be used in the form of hydrates or may contain other solvents used for crystallization.
(ａ)ＤＮＡトポイソメラーゼ阻害剤および(ｂ)ＩＡＰ阻害剤(ここで、両活性成分は各々遊離形または薬学的に許容される塩の形で存在する)および所望により少なくとも１個の薬学的に許容される担体を含む組み合わせ剤は、以後、「本発明の組み合わせ剤」と呼ぶ。 (a) a DNA topoisomerase inhibitor and (b) an IAP inhibitor, where both active ingredients are each present in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable The combination containing the carrier is hereinafter referred to as “the combination of the present invention”.
「本発明の組み合わせ剤」の薬理学的活性は、例えば、本質的に下記の通りの臨床試験または試験法により証明し得る。適当な臨床試験は、例えば、進行した固形腫瘍患者におけるオープンラベル非無作為、用量漸増試験である。このような試験は、特に、「本発明の組み合わせ剤」の活性成分の相乗活性を証明する。増殖性疾患に対する有益な効果は、直接、これらの試験の結果を介して、または、当業者に既知の通りの試験設計の変更により、決定できる。このような試験は、特に、活性成分を使用した単剤療法と「本発明の組み合わせ剤」の効果を比較するのに適している。好ましくは、組み合わせパートナー(ａ)を固定された用量で投与し、組み合わせパートナー(ｂ)の用量を、最大耐量に到達するまで漸増する。 The pharmacological activity of the “combination agent of the present invention” can be demonstrated, for example, by a clinical test or test method essentially as described below. A suitable clinical trial is, for example, an open label non-random, dose escalation trial in patients with advanced solid tumors. Such a test in particular demonstrates the synergistic activity of the active ingredients of the “combination agent according to the invention”. Beneficial effects on proliferative diseases can be determined directly through the results of these tests or by modification of the test design as known to those skilled in the art. Such a test is particularly suitable for comparing the effects of monotherapy using the active ingredient and the “combination agent of the invention”. Preferably, combination partner (a) is administered at a fixed dose and the dose of combination partner (b) is gradually increased until the maximum tolerated dose is reached.
イリノテカンは、例えば、商品名CAMPTOSARＴＭの下に、例えば市販の形で、投与できる。トポテカンは、例えば、商品名HYCAMTINＴＭの下に、例えば市販の形で、投与できる。エトポシドは、例えば、商品名ETOPOPHOSＴＭの下に、例えば市販の形で、投与できる。テニポシドは、例えば、商品名VM 26-BRISTOLＴＭの下に、例えば市販の形で、投与できる。ドキソルビシンは、例えば、商品名ADRIBLASTINＴＭの下に、例えば市販の形で、投与できる。エピルビシンは、例えば、商品名FARMORUBICINＴＭの下に、例えば市販の形で、投与できる。イダルビシンは、例えば、商品名ZAVEDOSＴＭの下に、例えば市販の形で、投与できる。ミトキサントロンは、例えば、商品名NOVANTRONＴＭの下に、例えば市販の形で、投与できる。 Irinotecan can be administered, eg, in the form as it is marketed, eg under the trademark CAMPTOSAR ™ . Topotecan can be administered, eg, in the form as it is marketed, eg under the trademark HYCAMTIN ™ . Etoposide can be administered, eg, in the form as it is marketed, eg under the trademark ETOPOPHOS ™ . Teniposide can be administered, eg, in the form as it is marketed, eg under the trademark VM 26-BRISTOL ™ . Doxorubicin can be administered, eg, in the form as it is marketed, eg under the trademark ADRIBLASTIN ™ . Epirubicin can be administered, eg, in the form as it is marketed, eg under the trademark FARMORUBICIN ™ . Idarubicin can be administered, eg, in the form as it is marketed, eg under the trademark ZAVEDOS ™ . Mitoxantrone can be administered, eg, in the form as it is marketed, eg under the trademark NOVANTRON ™ .
増殖性疾患に対して治療的有効量の、「本発明の組み合わせ剤」を含む医薬組成物の提供が本発明の一つの目的である。この組成物において、組み合わせパートナー(ａ)および(ｂ)は、一緒に、交互にまたは別々に、１個の組み合わせ単位投与形態として、または、２個の別々の単位投与形態として投与できる。本単位投与形態はまた固定された組み合わせであり得る。 It is an object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of “the combination of the present invention” for proliferative diseases. In this composition, the combination partners (a) and (b) can be administered together, one after the other or separately as one combined unit dosage form or as two separate unit dosage forms. The unit dosage form can also be a fixed combination.
本発明の医薬組成物は、それ自体既知の方法で製造でき、ヒトを含む哺乳動物(温血動物)に経腸、例えば経口または直腸、および非経腸投与するのに適したものである。あるいは、本薬剤を別々に投与するとき、一方が直腸製剤であってよく、他方が非経腸的に投与してよい。 The pharmaceutical composition of the present invention can be produced by a method known per se, and is suitable for enteral, eg, oral or rectal, and parenteral administration to mammals including humans (warm-blooded animals). Alternatively, when the agents are administered separately, one may be a rectal formulation and the other may be administered parenterally.
本新規医薬組成物は、例えば、約１０％から約１００％、好ましくは約２０％から約６０％の活性成分を含む。直腸または非経腸投与用の組み合わせ治療のための医薬製剤は、例えば、糖衣錠、錠剤、カプセルまたは坐薬、およびさらにアンプルのような単位投与形態のものである。特記されない限り、これらはそれ自体既知の方法で、例えば慣用の混合、造粒、糖コーティング、溶解または凍結乾燥工程の手段により製造する。各投与形態の個々の用量に含まれる組み合わせパートナーの単位含量は、必要な有効量が複数の投与単位の投与により達成できるため、それ自体で有効量を構成する必要はないことは認識されよう。 The novel pharmaceutical compositions contain, for example, from about 10% to about 100%, preferably from about 20% to about 60% active ingredient. Pharmaceutical formulations for combination therapy for rectal or parenteral administration are, for example, those in unit dosage forms such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. Unless otherwise stated, these are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar coating, dissolving or lyophilizing processes. It will be appreciated that the unit content of the combination partner included in the individual doses of each dosage form does not need to constitute an effective amount by itself because the required effective amount can be achieved by administration of multiple dosage units.
経口投与形態の組成物の製造において、例えば、水、グリコール、油、アルコール、香味剤、防腐剤、着色剤のような通常の医薬媒体；または、例えば、粉末、カプセルおよび錠剤のような固体製剤の場合はデンプン、糖、微結晶性セルロース、希釈剤、造粒剤、滑剤、結合剤、崩壊剤などの担体のいずれかを用いてよく、固体経口製剤が液体製剤よりも好ましい。その投与の容易さのため、錠剤およびカプセルが、最も有利な経口固体単位形態を表し、この場合、固体医薬担体を明らかに用いる。 In the manufacture of compositions for oral dosage form, for example, conventional pharmaceutical media such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents; or solid formulations such as, for example, powders, capsules and tablets In this case, any of carriers such as starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binder and disintegrant may be used, and solid oral preparation is preferable to liquid preparation. Because of their ease of administration, tablets and capsules represent the most advantageous oral solid unit form, in which case solid pharmaceutical carriers are obviously employed.
特に、治療的有効量の「本発明の組み合わせ剤」の組み合わせパートナーの各々を、同時にまたは任意の順番で連続的に投与でき、そして、該成分を別々にまたは固定された組み合わせとして投与できる。例えば、本発明の増殖性疾患の進行遅延または処置のための方法は、(ｉ)遊離形または薬学的に許容される塩形の第一組み合わせパートナーを投与し、そして(ii)遊離形または薬学的に許容される塩形態の第二組み合わせパートナーを、同時にまたは任意の順番で連続的に、併用で治療的有効量で、好ましくは相乗的有効量で投与することを含む。「本発明の組み合わせ剤」の個々の組み合わせパートナーは、治療経過中に異なる時点で別々に、または、同時に別々のまたは１個の組み合わせ形態として投与できる。さらに、投与なる用語は、インビボで組み合わせパートナーそれ自体に変換する組み合わせパートナーのプロドラッグの使用も包含する。本発明は、故に、同時または交互処置の全てのこのようなレジメンを包含すると理解すべきであり、そして、用語“投与する”は、それに応じて解釈すべきである。 In particular, each of the combination partners of a therapeutically effective amount of “a combination of the invention” can be administered simultaneously or sequentially in any order, and the components can be administered separately or as a fixed combination. For example, the method for delaying or treating the proliferative disease of the present invention comprises (i) administering a first combination partner in free form or pharmaceutically acceptable salt form, and (ii) free form or pharmaceutical Administering a second combination partner in a pharmaceutically acceptable salt form simultaneously or sequentially in any order, in combination, in a therapeutically effective amount, preferably in a synergistically effective amount. The individual combination partners of the “combination agents of the invention” can be administered separately at different times during the course of treatment, or simultaneously in separate or single combination forms. Furthermore, the term administration also encompasses the use of combination partner prodrugs that convert to the combination partner itself in vivo. The present invention should therefore be understood to encompass all such regimes of simultaneous or alternating treatment, and the term “administering” should be construed accordingly.
「本発明の組み合わせ剤」は、組み合わせ製剤または医薬組成物であり得る。 The “combination agent of the present invention” can be a combined preparation or a pharmaceutical composition.
さらに、本発明は、増殖性疾患を有する温血動物の処置法であって、該動物に、該増殖性疾患に対する治療的有効量の「本発明の組み合わせ剤」を投与することを含む、方法に関する。 Furthermore, the present invention provides a method for treating a warm-blooded animal having a proliferative disease, the method comprising administering to the animal a therapeutically effective amount of the “combination agent of the present invention” for the proliferative disease. About.
さらに、本発明は、増殖性疾患の処置のためのおよび増殖性疾患の処置用医薬の製造のための、「本発明の組み合わせ剤」の使用に関する。 Furthermore, the present invention relates to the use of “the combination of the present invention” for the treatment of proliferative diseases and for the manufacture of a medicament for the treatment of proliferative diseases.
さらに、本発明は、活性成分として「本発明の組み合わせ剤」を、増殖性疾患の進行遅延または処置のためのそれらの同時、別々または連続使用のための指示書と共に含む、商業的包装物を提供する。 Furthermore, the present invention comprises a commercial package comprising “the combination of the present invention” as an active ingredient together with instructions for their simultaneous, separate or sequential use for the delaying or treatment of proliferative diseases. provide.
本発明の好ましい態様は、
・化合物Ｃおよびトポテカン、
・カンプトテシンおよび化合物Ｄ、または
・化合物Ｃおよびカンプトテシン
を含む組み合わせにより表される。
A preferred embodiment of the present invention is:
Compound C and topotecan,
• Represented by camptothecin and compound D, or • a combination comprising compound C and camptothecin.
さらなる局面において、本発明は
・(ａ)「本発明の組み合わせ剤」(ここで、両活性成分はいずれの場合も遊離形もしくはそれらの薬学的に許容される塩またはそれらの任意の水和物の形で存在する)および所望により少なくとも１個の薬学的に許容される担体を含む；同時、別々または連続使用のための組み合わせ剤；
・併用で増殖性疾患に対する有効量の「本発明の組み合わせ剤」および少なくとも１個の薬学的に許容される担体を含む医薬組成物；
・増殖性疾患の処置のための「本発明の組み合わせ剤」の使用；
・増殖性疾患の処置用医薬の製造のための「本発明の組み合わせ剤」の使用；
・ＩＡＰ阻害剤が化合物Ｃおよび化合物Ｄから選択されるものである、「本発明の組み合わせ剤」の使用；
・ＤＮＡトポイソメラーゼ阻害剤がトポイソメラーゼＩ阻害剤である、「本発明の組み合わせ剤」の使用；および
・ＤＮＡトポイソメラーゼ阻害剤がトポイソメラーゼII阻害剤である、「本発明の組み合わせ剤」の使用。
In a further aspect, the present invention provides: (a) “the combination of the present invention” (wherein both active ingredients are in free form or their pharmaceutically acceptable salts or any hydrates thereof) And optionally at least one pharmaceutically acceptable carrier; a combination for simultaneous, separate or sequential use;
-A pharmaceutical composition comprising an effective amount for a proliferative disease in combination and "the combination of the invention" and at least one pharmaceutically acceptable carrier;
The use of a “combination agent of the invention” for the treatment of proliferative diseases;
Use of the “combination agent of the present invention” for the manufacture of a medicament for the treatment of proliferative diseases;
The use of a “combination agent according to the invention”, wherein the IAP inhibitor is selected from compound C and compound D;
Use of the “combination agent of the present invention” in which the DNA topoisomerase inhibitor is a topoisomerase I inhibitor; and • Use of the “combination agent of the present invention” in which the DNA topoisomerase inhibitor is a topoisomerase II inhibitor.
特に、本発明は、(ａ)トポイソメラーゼＩ阻害剤および(ｂ)ＩＡＰ阻害剤を含む組み合わせ剤に関する。 In particular, the present invention relates to a combination comprising (a) a topoisomerase I inhibitor and (b) an IAP inhibitor.
さらに、特に、本発明は、(ａ)１個以上の単位投与形態のトポイソメラーゼＩ阻害剤および(ｂ)１個以上の単位投与形態のＩＡＰ阻害剤を含む、組み合わせ製剤に関する。 More particularly, the invention relates to a combination formulation comprising (a) one or more unit dosage forms of a topoisomerase I inhibitor and (b) one or more unit dosage forms of an IAP inhibitor.
さらに、特に、本発明は、増殖性疾患の処置用医薬の製造のための、(ａ)トポイソメラーゼＩ阻害剤および(ｂ)ＩＡＰ阻害剤を含む、組み合わせ剤の使用に関する。 More particularly, the invention relates to the use of a combination comprising (a) a topoisomerase I inhibitor and (b) an IAP inhibitor for the manufacture of a medicament for the treatment of proliferative diseases.
「本発明の組み合わせ剤」に用いる組み合わせパートナーの各々の有効量は、用いる特定の化合物または医薬組成物、投与の形態、処置している状態、処置している状態の感受性に依存して変化し得る。故に、投与レジメンは、「本発明の組み合わせ剤」を、投与経路ならびに患者の腎臓および肝臓機能を含む種々の因子に従って選択する。通常の技術の医師、臨床医または獣医師は、状態の予防、回復または進行停止に必要な単独の活性成分の有効量を容易に決定し、処方できる。毒性を伴わない効果を発現する活性成分濃度の範囲を達成するための最適な詳細は、標的部位の活性成分の利用能の動態に基づく投与計画を必要とする。 The effective amount of each combination partner used in the “combinants of the invention” will vary depending on the particular compound or pharmaceutical composition used, the mode of administration, the condition being treated, and the sensitivity of the condition being treated. obtain. Therefore, the dosing regimen is selected according to various factors including the route of administration and the kidney and liver function of the patient. The ordinary skill physician, clinician or veterinarian can readily determine and prescribe the effective amount of the single active ingredient required to prevent, recover or stop progression of the condition. Optimal details to achieve a range of active ingredient concentrations that produce non-toxic effects requires a dosing regimen based on the kinetics of the active ingredient's availability at the target site.
「本発明の組み合わせ剤」に用いる組み合わせパートナーを単剤として市販の形で適応するとき、それらの投与量および投与形態は、他のことが記載されていない限り、ここに記載の有効な効果をもたらすために、各市販薬の添付文書に提供されている情報に従い得る。 When the combination partner used in the “combination agent of the present invention” is applied in a commercially available form as a single agent, their dosages and dosage forms have the effective effects described herein unless otherwise stated. To provide, you can follow the information provided in the package insert for each over-the-counter drug.
イリノテカンは、ヒトに、約５０から３５０mg／ｍ２／日で変化する用量範囲で投与できる。 Irinotecan can be administered to humans in dosage ranges that vary from about 50 to 350 mg / m 2 / day.
トポテカンは、ヒトに、約１から５mg／ｍ２／日で変化する用量範囲で投与できる。 Topotecan can be administered to humans in a dosage range that varies from about 1 to 5 mg / m 2 / day.
リン酸エトポシドは、ヒトに、約２５から１１５mg／ｍ２／日変化する用量範囲で、例えば５６.８または１１３.６mg／ｍ２で日で投与できる。 Etoposide phosphate can be administered to humans daily at a dose range varying from about 25 to 115 mg / m 2 / day, for example, 56.8 or 113.6 mg / m 2 .
テニポシドは、ヒトに、約２週間毎に、約７５から１５０mgで変化する用量範囲で投与できる。 Teniposide can be administered to humans in a dosage range varying from about 75 to 150 mg about every two weeks.
ドキソルビシンは、ヒトに、約１０から１００mg／ｍ２／日で変化する用量範囲で、例えば２５または５０mg／ｍ２日で投与できる。 Doxorubicin can be administered to humans in a dosage range that varies from about 10 to 100 mg / m 2 / day, for example 25 or 50 mg / m 2 days.
エピルビシンは、ヒトに、約１０から２００mg／ｍ２／日で変化する用量範囲で投与できる。 Epirubicin can be administered to humans in dosage ranges varying from about 10 to 200 mg / m 2 / day.
イダルビシンは、ヒトに、約０.５から５０mg／ｍ２／日で変化する用量範囲で投与できる。 Idarubicin can be administered to humans in a dosage range that varies from about 0.5 to 50 mg / m 2 / day.
ミトキサントロンは、ヒトに、約２.５から２５mg／ｍ２／日で変化する用量範囲で投与できる。 Mitoxantrone can be administered to humans in a dosage range that varies from about 2.5 to 25 mg / m 2 / day.
下記実施例は、上記の本発明を説明する；しかしながら、それらは、本発明の範囲を限定することを意図しない。「本発明の組み合わせ剤」の有益な効果は、関連分野の当業者にそれ自体既知の他の試験モデルによりまた決定できる。 The following examples illustrate the invention described above; however, they are not intended to limit the scope of the invention. The beneficial effect of “the combination of the invention” can also be determined by other test models known per se to the person skilled in the relevant art.
実施例１：黒色腫モデルにおいて、化合物Ｄ(２５０nM)は、対照の約９０％の増殖を示し、カンプトテシン(５nM)は対照の約５０％の増殖を示すが、一方化合物Ｄ(２５０nM)とカンプトテシン(５nM)の組み合わせは、対照の３％未満の増殖を示す。 Example 1: In a melanoma model, compound D (250 nM) shows about 90% growth of control and camptothecin (5 nM) shows about 50% growth of control, whereas compound D (250 nM) and camptothecin The (5 nM) combination shows less than 3% growth of the control.
実施例２：***腫瘍モデルにおいて、化合物Ｃおよびトポテカン(１nM)の両方は個々でカスパーゼ−３活性を、対照の２倍未満で上昇させる。カスパーゼ−３活性のほぼ１２倍の上昇が、同用量の化合物Ｃと、約１nM濃度のトポテカンで見られる。 Example 2: In a breast tumor model, both Compound C and topotecan (1 nM) individually increase caspase-3 activity in less than twice the control. An approximately 12-fold increase in caspase-3 activity is seen with the same dose of Compound C and about 1 nM concentration of topotecan.
実施例３：転移性黒色腫細胞系Ａ２０５８において、下記組み合わせ指数(ＣＩ)値が、カンプトテシンと化合物Ｃ、カンプトテシンと化合物Ｄで行う相乗的実験から得られる。
各化合物のＣＩ値は、各組み合わせパートナーのＥＤ９０、ＥＤ７５およびＥＤ５０で計算する。
Example 3 In the metastatic melanoma cell line A2058, the following combination index (CI) values are obtained from synergistic experiments performed with camptothecin and compound C, camptothecin and compound D.
CI values for each compound are calculated with ED90, ED75 and ED50 for each combination partner.
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| PCT/EP2005/001180 WO2005074989A2 (en) | 2004-02-05 | 2005-02-04 | Combination of a dna topoisomerase inhibitor and an iap inhibitor |
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| CA2574040C (en) | 2004-07-15 | 2014-05-06 | Tetralogic Pharmaceuticals Corporation | Iap binding compounds |
| CA2598995C (en) | 2005-02-25 | 2014-07-15 | Stephen M. Condon | Dimeric iap inhibitors |
| JP4954983B2 (en) | 2005-05-18 | 2012-06-20 | ファーマサイエンス・インコーポレイテッド | BIR domain binding compound |
| BRPI0617751A2 (en) | 2005-10-25 | 2011-08-02 | Aegera Therapeutics Inc | iap bir domain binding compounds |
| TWI504597B (en) | 2006-03-16 | 2015-10-21 | Pharmascience Inc | Iap bir domain binding compounds |
| EP2049524A2 (en) | 2006-07-24 | 2009-04-22 | Tetralogic Pharmaceuticals Corporation | Iap inhibitors |
| US7985735B2 (en) | 2006-07-24 | 2011-07-26 | Tetralogic Pharmaceuticals Corporation | Dimeric IAP inhibitors |
| US8283372B2 (en) | 2009-07-02 | 2012-10-09 | Tetralogic Pharmaceuticals Corp. | 2-(1H-indol-3-ylmethyl)-pyrrolidine dimer as a SMAC mimetic |
| WO2011098904A1 (en) | 2010-02-12 | 2011-08-18 | Aegera Therapeutics, Inc. | Iap bir domain binding compounds |
| UY33236A (en) | 2010-02-25 | 2011-09-30 | Novartis Ag | DIMERIC INHIBITORS OF THE IAP |
| UY33794A (en) | 2010-12-13 | 2012-07-31 | Novartis Ag | DIMERIC INHIBITORS OF THE IAP |
| WO2015109391A1 (en) | 2014-01-24 | 2015-07-30 | Children's Hospital Of Eastern Ontario Research Institute Inc. | Smc combination therapy for the treatment of cancer |
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- 2005-02-04 AU AU2005210137A patent/AU2005210137B2/en not_active Ceased
- 2005-02-04 KR KR1020067015819A patent/KR20060126548A/en not_active Application Discontinuation
- 2005-02-04 RU RU2006131553/15A patent/RU2006131553A/en not_active Application Discontinuation
- 2005-02-04 WO PCT/EP2005/001180 patent/WO2005074989A2/en active Application Filing
- 2005-02-04 US US10/587,758 patent/US20110251134A1/en not_active Abandoned
- 2005-02-04 JP JP2006551818A patent/JP2007520522A/en active Pending
- 2005-02-04 EP EP05707223A patent/EP1713542A2/en not_active Withdrawn
- 2005-02-04 CN CNA2005800030364A patent/CN1953744A/en active Pending
- 2005-02-04 CA CA002552937A patent/CA2552937A1/en not_active Abandoned
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| CA2552937A1 (en) | 2005-08-18 |
| US20110251134A1 (en) | 2011-10-13 |
| BRPI0507482A (en) | 2007-07-17 |
| AU2005210137A1 (en) | 2005-08-18 |
| KR20060126548A (en) | 2006-12-07 |
| WO2005074989A2 (en) | 2005-08-18 |
| WO2005074989A3 (en) | 2006-11-09 |
| RU2006131553A (en) | 2008-03-10 |
| EP1713542A2 (en) | 2006-10-25 |
| AU2005210137B2 (en) | 2009-06-04 |
| CN1953744A (en) | 2007-04-25 |
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